Memantine, 10 mg 30 pcs.

Disruption of glutamatergic neurotransmission, particularly NMDA receptor function, contributes to both the symptoms and progression of neurodegenerative dementia.

Memantine is a potential-dependent, moderately affinity-dependent, noncompetitive inhibitor of NMDA receptors. The drug modulates the pathological increase of glutamate, which can lead to neuronal dysfunction. It improves cognitive processes and increases daily activity.

Pharmacokinetics

Intake

After oral administration, memantine is quickly and completely absorbed from the gastrointestinal tract. Absolute bioavailability is about 100%. Maximum concentration (Cmax) in plasma is reached within 3-8 hours. Food intake does not affect the absorption of memantine.

Distribution

The daily dose of 20 mg produces a constant plasma concentration of memantine in the range 70-150 ng/mL (0.5-1 μmol) with marked individual variation. In daily doses of 5 to 30 mg, the average ratio of the drug content in cerebrospinal fluid to that in blood serum was 0.52. The volume of distribution is 10 l/kg. About 45% of memantine is bound to plasma proteins.

Metabolism

About 80% of memantine taken orally circulates unchanged. The major metabolites in humans are N-3,5-dimethylgludantane, a mixture of isomers
4- and 6-hydroxymemantine and l-nitroso-3,5-dimethyladamantane. None of these metabolites has NMDA-antagonistic activity.

In in vitro studies, no involvement of cytochrome P450 system isoenzymes in the metabolism of memantine was detected.

In an oral study of labeled 14C-memantine, more than 84% of the dose was excreted within 20 days, and more than 99% was excreted by the kidneys.

The excretion of memantine is monoexponential with a half-life (T½) of 60 to 100 hours. Total clearance is 170 ml/min/1.73 m2, with part of the total renal clearance achieved by tubular secretion.

There is also a process of tubular reabsorption in the kidneys, probably mediated by proteins involved in cation transport. The rate of renal clearance of memantine may decrease when urine is alkaline to pH 7-9. Alkalinization of the urine can be the result of dramatic changes in diet, such as switching to vegetarianism, or taking plenty of alkaline gastric buffers.

Linearity

Volunteer studies have demonstrated linear pharmacokinetics over a dose range of 10 to 40 mg.

The relationship between pharmacokinetics and pharmacodynamics

When using memantine at a dose of 20 mg daily, the cerebrospinal fluid content of the drug corresponds to the ki value (inhibition constant) of memantine, which is 0.5 μmol of the drug in the frontal lobe of the cerebral cortex.

Indications

Moderate to severe dementia of the Alzheimer’s type.

Pharmacological effect

Impaired glutamatergic neurotransmission, particularly NMDA receptor function, contributes to both the symptoms and progression of neurodegenerative dementia.

Memantine is a voltage-dependent, moderate affinity, non-competitive inhibitor of NMDA receptors. The drug modulates the pathological increase in glutamate, which can lead to neuronal dysfunction. Improves cognitive processes, increases daily activity.

Pharmacokinetics

Suction

After oral administration, memantine is quickly and completely absorbed from the gastrointestinal tract. Absolute bioavailability is about 100%. The maximum concentration (Cmax) in the blood plasma is reached within 3-8 hours. Food intake does not affect the absorption of memantine.

Distribution

When taking a daily dose of 20 mg, a constant concentration of memantine in the blood plasma is created in the range of 70-150 ng/ml (0.5-1 µmol) with pronounced individual variations. When using daily doses from 5 to 30 mg, the average ratio of the drug content in the cerebrospinal fluid to the content in the blood serum was 0.52. The volume of distribution is 10 l/kg. About 45% of memantine is bound to plasma proteins.

Metabolism

About 80% of memantine taken orally circulates unchanged. The main metabolites in humans are N-3,5-dimethylgludantan, a mixture of isomers
4- and 6-hydroxymemantine and l-nitroso-3,5-dimethyladamantane. None of these metabolites have NMDA antagonistic activity.

In vitro studies did not reveal the participation of isoenzymes of the cytochrome P450 system in the metabolism of memantine.

In a study of oral 14C-labeled memantine, more than 84% of the dose was eliminated within 20 days, and more than 99% was excreted by the kidneys.

Removal

Memantine elimination is monoexponential with a half-life (T½) of 60 to 100 hours. The total clearance is 170 ml/min/1.73 m2, with part of the total renal clearance achieved through tubular secretion.

Also in the kidneys there is a process of tubular reabsorption, probably mediated by proteins involved in cation transport. The rate of renal clearance of memantine may be reduced when urine is alkalinized to pH 7-9. Alkalinization of urine can be the result of sudden changes in diet, such as becoming a vegetarian, or heavy intake of alkaline gastric buffers.

Linearity

Studies in volunteers have demonstrated linear pharmacokinetics over the dose range of 10 to 40 mg.

Relationship between pharmacokinetics and pharmacodynamics

When using memantine at a dose of 20 mg per day, the content of the drug in the cerebrospinal fluid corresponds to the ki value (inhibition constant) of memantine, which is 0.5 µmol of the drug in the frontal lobe of the cerebral cortex.

Special instructions

The optimal dose is achieved gradually, with the dose increasing every week.

In patients with epilepsy, a history of seizures, or in patients predisposed to epilepsy, memantine should be used with caution.

Concomitant use of memantine with an NMDA receptor antagonist such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act on the same receptor system as memantine, so adverse reactions (mainly central nervous system related) may occur more frequently and be severe.

The presence of a number of factors that can increase urine pH in patients requires careful medical monitoring. These include: sudden changes in diet, such as switching from a meat-based diet to a vegetarian diet, or high consumption of alkaline gastric buffer solutions. Also, renal tubular acidosis or severe urinary tract infections caused by Proteus spp can lead to an increase in urine pH. Conditions that increase urinary pH may decrease the excretion of memantine by the urinary system, resulting in increased plasma memantine concentrations.

Most clinical studies excluded patients with a history of myocardial infarction or decompensated chronic heart failure
(III-IV functional class according to the NYHA classification) or uncontrolled arterial hypertension. Therefore, data on the use of memantine in such patients is limited, and the use of Memantine should be carried out under close medical supervision.

Most people with Alzheimer’s disease are 65 years or older. In clinical trials of memantine, the average age of patients was approximately 76 years: more than 90% of patients were 65 years of age or older, 60% were 75 years of age or older, and 12% were over 85 years of age. There were no clinically significant differences in most adverse events between the groups of patients ≥ 65 years and < 65 years.

No dose adjustment is required in patients with mild to moderate renal impairment. Dose reduction is recommended in patients with severe renal impairment.

No dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).

The influence of a medicinal product for medical use on the ability to drive vehicles and machinery

Patients with Alzheimer’s disease in the stages of moderate to severe dementia usually have impaired ability to drive vehicles and operate complex machinery. In addition, memantine can cause a change in the speed of psychomotor reaction, so patients should refrain from driving vehicles or operating complex machinery.

Active ingredient

Memantine

Composition

1 film-coated tablet, 10 mg contains:

Tablet core composition:

Active ingredient: memantine hydrochloride – 10.0 mg.

Excipients: microcrystalline siliconized cellulose, croscarmellose sodium, sodium stearyl fumarate.

Tablet shell composition: opadry II white (33G28435) (hypromellose, titanium dioxide, lactose monohydrate, triacetin, macrogol).

Contraindications

Hypersensitivity to memantine or other components of the drug; lactose intolerance, lactase deficiency, glucose-galactose malabsorption; severe liver failure (class C on the Child-Pugh scale); children and adolescents under 18 years of age (efficacy and safety have not been established); pregnancy and breastfeeding period.

With caution

Prescribed to patients with thyrotoxicosis, epilepsy, convulsions (including a history), myocardial infarction, heart failure, simultaneous use of NMDA receptor antagonists (amantadine, ketamine, dextromethorphan); the presence of factors that increase urine pH (sudden change of diet (switching from meat to vegetarian), heavy intake of alkaline gastric buffers, severe urinary tract infections (caused by Proteus bacteria), renal tubular acidosis, uncontrolled arterial hypertension, renal failure, mild or moderate liver failure (class A and B according to the Child-Pugh classification).

Side Effects

The incidence of side effects is classified according to clinical manifestations (according to damage to certain organ systems) and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000, including isolated reports), frequency unknown (currently there are no data on the prevalence of side effects).

Infectious and parasitic diseases: infrequently – fungal infections.

Immune system disorders: often – hypersensitivity to the drug.

Mental disorders: often – drowsiness; infrequently – confusion, hallucinations (mainly observed in patients with Alzheimer’s disease at the stage of severe dementia); frequency unknown – psychotic reactions (isolated cases, reports of which were received in the post-registration period).

Nervous system disorders: often – dizziness, imbalance; infrequently – gait disturbance; very rarely – convulsions.

Cardiovascular system disorders: often – arterial hypertension; uncommon – heart failure, venous thrombosis/thromboembolism.

Disorders of the respiratory system, chest and mediastinal organs: often – shortness of breath.

Gastrointestinal disorders: often – constipation; uncommon – nausea, vomiting; frequency unknown – pancreatitis (isolated cases, reports of which were received in the post-registration period).

Disorders of the liver and biliary tract: often – increased biochemical indicators of liver function; frequency unknown – hepatitis.

General disorders and disorders at the injection site: often – headache, infrequently – fatigue.

With Alzheimer’s disease, patients may experience depression, suicidal thoughts, and suicide attempts. These effects have been reported in clinical practice in patients taking memantine.

Experience of post-marketing use of the drug

The following are adverse events described in spontaneous reports during post-marketing use of memantine, for which a causal relationship with the drug cannot be excluded: agranulocytosis, leukopenia (including neutropenia), pancytopenia, thrombocytopenia, thrombocytopenic purpura, acute renal failure, Stevens-Johnson syndrome.

Interaction

When used simultaneously with levodopa drugs, dopamine receptor antagonists, and m-anticholinergic blockers, the effect of the latter may be enhanced.

When used simultaneously with barbiturates and neuroleptics, the effect of the latter may decrease.

When used together, it can change (increase or decrease) the effect of dantrolene and baclofen, so the doses of the drugs should be selected individually.

Concomitant use with amantadine should be avoided due to an increased risk of developing psychosis. This risk is also common with ketamine and dectromethorphan. A case of risk of such interaction between memantine and phenytoin has been described. These drugs are chemically related NMDA receptor antagonists.

It is possible that the plasma concentrations of cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine may increase when taken simultaneously with memantine.

A decrease in the concentration of hydrochlorothiazide is possible when taken simultaneously with memantine.

There may be an increase in INR (international normalized ratio) in patients taking oral anticoagulants (warfarin). Although a cause-and-effect relationship has not been established, close monitoring of prothrombin time and INR is recommended in patients concomitantly taking oral anticoagulants.

There is a possibility of decreased serum concentrations of hydrochlorothiazide when administered concomitantly with memantine or any combination containing hydrochlorothiazide. Memantine may increase the excretion of hydrochlorothiazide.

Concomitant use with antidepressants, selective serotonin reuptake inhibitors and monoamine oxidase inhibitors requires careful monitoring of patients.

There are no pharmacokinetic interactions between memantine and glibenclamide, metformin or donepezil.

There was no significant effect of memantine on the pharmacokinetics of galantamine.

Memantine does not inhibit the activity of CYP isoenzymes 1A2, 2A6, 2C9, 2D6, 2E1, 3A, flavin monooxidase, epoxide hydrolase and sulfation in vitro.

Overdose

There are limited data on overdose obtained from clinical trials and post-marketing experience with memantine.

Symptoms: A relatively large overdose (200 mg once and 105 mg per day for 3 days) was manifested by fatigue, weakness and/or diarrhea, or there were no symptoms. In patients with an overdose of less than 140 mg or with an unknown dose, symptoms such as confusion, hypersomnia, drowsiness, dizziness, agitation, aggression, hallucinations, gait disturbance, vomiting, and diarrhea were observed.

Taking 2000 mg of memantine did not lead to death, but was accompanied by disorders of the nervous system (coma for 10 days, then diplopia and agitation). After symptomatic treatment and plasmapheresis, recovery occurred without further complications.

In another reported case, the patient also recovered. After taking 400 mg of memantine orally, he experienced the following disorders of the central nervous system: anxiety, psychosis, visual hallucinations, decreased seizure threshold, drowsiness, stupor, unconsciousness.

Treatment: gastric lavage, activated charcoal, urine acidification, forced diuresis, symptomatic therapy. There is no specific antidote. If signs and symptoms of general hyperstimulation of the central nervous system appear, symptomatic therapy should be carried out with caution.

Storage conditions

In a place protected from light at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life

4 years.

Do not use after expiration date.

Manufacturer

Izvarino Pharma, Russia